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Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-β involves functional cooperation with p300/CBP transcriptional coactivators


Transforming growth factor-β (TGF-β) stimulation of Type I collagen gene (COL1A2) transcription involves the Smad signal transduction pathway, but the mechanisms of Smad-mediated transcriptional activation are not fully understood. We now demonstrate that the ubiquitous transcriptional coactivators p300 and CREB-binding protein (CBP) enhanced basal as well as TGF-β- or Smad3-induced COL1A2 promoter activity, and stimulated the expression of endogenous Type I collagen. The adenoviral E1A oncoprotein abrogated stimulation of COL1A2 activity in transfected fibroblasts, and reduced the basal level of collagen gene expression. This effect was due to specific interaction of E1A with cellular p300/CBP because (a) a mutant form of E1A defective in p300 binding failed to abrogate stimulation, and (b) forced expression of p300/CBP restored the ability of TGF-β to stimulate COL1A2 promoter activity in the presence of E1A. The effect of p300 on COL1A2 transcription appeared to be due, in part, to its intrinsic acetyltransferase activity, as stimulation induced by a histone acetyltransferase-deficient mutant p300 was substantially reduced. Transactivation of COL1A2 by p300 involved the Smad signaling pathway, as Smad4-deficient cells failed to respond to p300, and stimulation was rescued by overexpression of Smad4. Furthermore, minimal constructs containing only the Smad-binding CAGACA element of COL1A2 were transactivated by p300 in the presence of TGF-β. These results indicate, for the first time, that the multifunctional p300/CBP coactivators play a major role in Smad-dependent TGF-β stimulation of collagen gene expression in fibroblasts.

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We are grateful to J Boyes, M Trojanowska, DM Livingston, R Janknecht, P Raychaudhuri, R Derynck, HF Lodish and E Moran for providing plasmids and recombinant adenovirus, and K Westcott and DR Olsen for human recombinant TGF-β1 and TGF-β2. We are especially indebted to P Raychaudhuri and L Platanias for helpful discussion. Supported by grants from the National Institute of Health (AR-42309 and AR-46390).

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Ghosh, A., Yuan, W., Mori, Y. et al. Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-β involves functional cooperation with p300/CBP transcriptional coactivators. Oncogene 19, 3546–3555 (2000).

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  • Type I collagen
  • transforming growth factor-β
  • Coactivators
  • p300/CBP
  • signal transduction
  • Smads

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